TOMOGRAPHIC SARCOPENIA PREDICTS ANASTOMOTIC LEAKS AND LONG-TERM SURVIVAL IN GASTRIC CANCER PATIENTS OPERATED WITH CURATIVE INTENT

ABSTRACT BACKGROUND: The preoperative nutritional state has prognostic postoperative value. Tomographic density and area of psoas muscle are validated tools for assessing nutritional status. There are few reports assessing the utility of staging tomography in gastric cancer patients in this field. AIMS: This study aimed to determine the influence of sarcopenia, measured by a preoperative staging computed tomography scan, on postoperative morbimortality and long-term survival in patients operated on for gastric cancer with curative intent. METHODS: This retrospective study was conducted from 2007 to 2013. The definition of radiological sarcopenia was by measurement of cross-sectional area and density of psoas muscle at the L3 (third lumbar vertebra) level in an axial cut of an abdominopelvic computed tomography scan (in the selection without intravascular contrast media). The software used was OsirixX version 10.0.2, with the tool “propagate segmentation”, and all muscle seen in the image was manually adjusted. RESULTS: We included 70 patients, 77% men, with a mean cross-sectional in L3 of 16.6 cm2 (standard deviation+6.1) and mean density of psoas muscle in L3 of 36.1 mean muscle density (standard deviation+7.1). Advanced cancers were 86, 28.6% had signet-ring cells, 78.6% required a total gastrectomy, postoperative surgical morbidity and mortality were 22.8 and 2.8%, respectively, and overall 5-year long-term survival was 57.1%. In the multivariate analysis, cross-sectional area failed to predict surgical morbidity (p=0.4) and 5-year long-term survival (p=0.34), while density of psoas muscle was able to predict anastomotic fistulas (p=0.009; OR 0.86; 95%CI 0.76–0.96) and 5-year long-term survival (p=0.04; OR 2.9; 95%CI 1.04–8.15). CONCLUSIONS: Tomographic diagnosis of sarcopenia from density of psoas muscle can predict anastomotic fistulas and long-term survival in gastric cancer patients treated with curative intent.


A QUEDA DA PRESSÃO PORTAL APÓS DESVASCULARIZAÇÃO ESOFAGOGÁSTRICA E ESPLENECTOMIA INFLUENCIA A VARIAÇÃO DO CALIBRE DAS VARIZES E AS TAXAS DE RESSANGRAMENTO NA ESQUISTOSSOMOSE NO SEGUIMENTO EM LONGO PRAZO?
Does the drop in portal pressure after esophagogastric devascularization and splenectomy variation of variceal calibers and the rebleeding rates in schistosomiasis in late follow-up?
Walter de Biase SILVA-NETO 1 , Claudemiro QUIRESE 1 , Eduardo Guimarães Horneaux de MOURA 2 , Fabricio Ferreira COELHO 3 , Paulo HERMAN 3 ABSTRACT -Background: The treatment of choice for patients with schistosomiasis with previous episode of varices is bleeding esophagogastric devascularization and splenectomy (EGDS) in association with postoperative endoscopic therapy. However, studies have shown varices recurrence especially after long-term follow-up. Aim: To assess the impact on behavior of esophageal varices and bleeding recurrence after post-operative endoscopic treatment of patients submitted to EGDS. Methods: Thirty-six patients submitted to EGDS portal pressure drop, more or less than 30%, and compared with the behavior of esophageal varices and the rate of bleeding recurrence. Results late post-operative varices caliber when compared the pre-operative data was observed despite an increase in diameter during follow-up that was controlled by endoscopic therapy. Conclusion variceal calibers when comparing pre-operative and early or late post-operative diameters. The comparison between the portal pressure drop and the rebleeding rates was also not

Perspectives
Knowing if a patient has sarcopenia in the staging CT allows us to prehabilitate them, to eventually reduce the anastomotic leakage risk and improve long-term survival.

Central Message
Radiological diagnosis of sarcopenia in patients with gastric cancer submitted to surgery with curative intent predicts anastomotic leaks and long-term survival.

Follow-up
The present study has 100% follow-up. The database was completed in a prospective manner; the survival update was carried out annually using the database of our hospital and the Chilean Civil Registry.

Statistical analysis
The distribution of variables was determined by the Shapiro-Wilk test. In accordance with this test, the continuous variables with parametric or nonparametric distribution were expressed as average and standard deviation (SD) or median and interquartile (IC 25%-75% ) ranges, respectively. The categorical variables were described in percentages. The Fisher's, chi-square, Student's t, and Wilcoxon rank-sum tests were used based on the characteristics and distribution of the variables. For the analytical statistical analysis, the Stata R 14 program was used, and p<0.05 was considered statistically significant. Univariate and multivariate analyses were performed, calculating the odds ratio (OR) with a 95% confidence interval (CI). The Kaplan-Meier and Cox regression were used to calculate survival curves. ROC curves were used to compare prognostic efficacy. The patients signed the informed consent form of the institution.

RESULTS
A total of 70 patients were included; their median age was 60.5 years (SD±13.6); 77% were men; 83.3% had comorbidities; smoking, hypertension, and diabetes were the most common conditions with 41.4, 34.2, and 17.1%, respectively.
Analysis of the psoas muscle at the L3 level in the staging CT scan showed a mean PD of 36.1 HU (SD±7.1) and a mean PA of 16.6 cm 2 (SD±6.1).
Notably, 86% of cancers were locally advanced, 58% had intestinal histology according to Lauren's classification, 28.6% had signet ring cells, 78.6% required total gastrectomy, and the mean lymph node dissection was 33.7 (SD±13.9). Staging details are explained in Table 1.
Postoperative morbidity and mortality were 22.8 and 2.8%, respectively. The details are explained in Table 2.
Overall long-term survival after five surgeries was achieved in 57.1% of patients ( Figure 2).
In the tomographic analysis of sarcopenia, the PA did not achieve statistical significance for any variable measured,

INTRODUCTION
A ccording to GLOBACAN in 2018, gastric cancer is the fifth most common neoplasm and the third most deadly neoplasm in the world 5 . Thanks to surgical technology, oncological drugs, and medical advances in critical care units; surgical morbimortality and long-term survival have improved significantly in the past 50 years 3,10,15,16 . Prognostic factors of postoperative evolution are well described, and the nutritional state has proven to be a relevant short-and longterm independent factors 12,15,18,20 .
Sarcopenia is defined as a loss of muscle strength, quality/ quantity, or reduced physical performance 9 ; these variables can be assessed in several ways 6,7,13 . Tomographic measurements of sarcopenia using the cross-sectional area (PA) and density (PD) of the psoas muscle are a validated practical approach due to their low cost and frequent use, especially in oncological patients 9 .
The aim of this study was to determine the influence of sarcopenia, measured by a preoperative staging CT (computed tomography) scan, on postoperative morbimortality and longterm survival in patients operated on for gastric cancer with curative intent.

METHODS Design
A retrospective analysis of the oncological database of a Chilean University Hospital (Universidad de Chile Clinical Hospital) from May 2007 to May 2013.
Considering the retrospective nature of the study and the privacy and anonymous analysis of all records, there was no need for institutional IRB approval.

Patients
All adult patients with gastric adenocarcinoma surgically treated with curative intent with in-hospital tomographic records (ICISview MR ) of the preoperative staging CT scan were included. Subtotal, total, and extended gastrectomies were included. All the patients were presented to the hospital oncology committee.
Exclusion criteria included gastrectomies due to benign lesions, Stage IV cancers according to the 7th edition TNM classification, R1 resections, type I and II Siewert esophagogastric junction cancers, palliative procedures, complete esophagogastrectomies, and emergency surgeries.

Definitions a)
The TNM classification was standardized using the AJCC 7th edition 18 Surgical mortality was defined as occurring from the moment of surgery up to postoperative day 90. c) Global survival was defined by patients' discharge from hospitals, eliminating surgical mortality. d) Long-term survival was defined as survival greater than 5 years postoperatively. e) Zero time for determining prognostic association was defined as gastrectomy.

Computed tomography measurement
All preoperative staging CTs were assessed by an expert radiologist with more than 5 years of experience. The mean cross-sectional area (cm 2 ) and mean muscle density (HU) were measured at the L3 (third lumbar vertebra) level in an axial cut of an abdominopelvic CT scan (in the selection without intravascular contrast media). The software used was OsirixX version 10.0.2, with the tool "propagate segmentation" adjusting manually all muscles seen in the image (Figure 1). whereas PD was associated with esophagojejunostomy (EJJ) leaks and SV5 (  (Figures 3, 4, and 5).      The multivariate analysis predicting EJJ leakages showed that PD was the only independent variable with prognostic power (p=0.009; OR 0.86; 95%CI 0.76-0.96). In contrast, analyzing longterm survival, the independent variables were age (p=0.04; OR: 0.65; 95%CI 0.91-0.99), locally advanced stage according to the TNM classification system (p=0.02; OR 0.08; 95%CI 0.009-0.7), and PD (p=0.04; OR 2.9; 95%CI 1.04-8.15) ( Table 4).

DISCUSSION
Sarcopenia is a well-known prognostic factor for shortand long-term postoperative outcomes; this pathology has different diagnostic methods and affects a specific group of patients, including oncological ones 9,26 .
Since the introduction of skeletal muscle index (SMI) with CT scan by Prado in 2008 25 , measurement of cross-sectional area and now density of the psoas muscle has proven to predict whole-body muscle accurately independent of body mass index (BMI), achieving short-and long-term prognostic value in different types of cancer 2,14,19,26,27,28 . Recently, a meta-analysis including more than 20,000 patients concluded that preoperative incidence of sarcopenia increases the likelihood of postoperative complications (p<0.001; RR 1.188; 95%CI 1.083-1.303) and overall mortality (p<0.001; HR 1.602; 95%CI 1.369-1.873) 28 .
The use of this practical and accurate tool in gastric cancer patients has been the subject of a few international reports, mostly from Asia 8,21,22,[28][29][30][31] and none from Latin American countries to the knowledge of the authors, this report should be the first coming from that region.
Even though diagnostic criteria and cutoff values for sarcopenia vary depending on country, sex, technology [magnetic resonance imaging (MRI) or CT], variables employed [skeletal muscle area (SMA), index (SMI), and mean attenuation (SMRA], the European Working Group on Sarcopenia in Older People recommends the use of two standard deviations below the mean reference value of young, healthy adults 9 . The cutoff value for sarcopenia in the US population according to SMA, SMI, and SMRA are 92.2 cm 2 , 34.4 cm 2 /m 2 , and 34.3 HU in women, and 144.3 cm 2 , 45.4 cm 2 /m 2 , and 38.5 HU in men, respectively 13 . With these parameters, the patients' rate with sarcopenia in our study was 44.6% (15.0% in women and 57.8% in men), which is higher than the average 34.7% rate in different types of gastrointestinal cancer patients in an international non-Latin American countries 16 but comparable to other specific gastric cancer reports 21,24,31 . This is an important factor in the discussion; the great heterogeneity of diagnostic criteria and indexes in the Caucasian and Asian literature, sometimes arbitrary, and the lack of this evidence in countries with developing economies, like the present study, makes it difficult to compare results and makes clear the need for scientific evidence.   Postoperative morbidity has been assessed by different studies 8,22,29,30,31 . This is exposed in Table 5. Most of these studies compared SMI with different criteria, and none of them analyzed mean PD; furthermore, most of them do not analyzed longterm survival, except a Chinese prospective study involving 937 patients admitted to radical gastrectomy for gastric cancer whose rate of postoperative morbidity and long-term result were comparable to the present report 29 .
Considering the heterogeneity in the diagnostic criteria of radiological sarcopenia, finding the best cutoff points to predict long-term postoperative outcomes is a key factor. In a Japanese 24 retrospective study of 177 patients with gastric cancer stages II-III admitted to oncological gastrectomy, five cutoff points of SMI (cm 2 /m 2 ) were assessed, and the prevalence of sarcopenia varied from 3 to 64%. The best SV5 predicting criteria were achieved with Martin's 23 cutoff point (SMI 53.0 for BMI>25 or 43.0 for BMI<25 in men, and 41.0 in women), with an SV5 of 48 vs. 68 months (p=0.005; HR 2.0; 95%CI 1. 24-3.24). Compared to that report, the present study interestingly achieved a better result with density than with muscle area. These results cannot be totally compared because the abovementioned article did not evaluate PD.
Considering that most patients with gastric cancer will need postoperative adjuvant therapy, it is vital to understand the impact of chemotherapy on the patient's nutrition status 28 . This topic has been studied; a muscle loss ≥9% during chemotherapy is associated with a shorter OS (p<0.001; HR 4.47; 95%CI 2.21−9.05) 4 , which, when added to preoperative sarcopenia, may have a synergic effect. This is especially important in therapeutic strategy if sarcopenia is diagnosed preoperatively, and additional effort in improving performance and nutritional status (prehabilitation) could benefit not only postoperative outcomes but also tolerance to chemotherapy and long-term survival. This hypothesis should be studied in future protocols.
In a palliative context, skeletal sarcopenia, diagnosed by Ct, has proved to be a valuable tool for predicting overall survival. Lee 21 reported a multivariate analysis of a cohort of 140 consecutive patients who underwent palliative chemotherapy for gastric adenocarcinoma; in that study, sarcopenia was defined as an L3 SMI <49 cm 2 /m 2 for men and <31 cm 2 /m 2 for women, using cutoff points specific for the Korean population. Radiological sarcopenia showed poor overall survival (6.8 vs. 10.3 months; p=0.033), which was confirmed in the multivariate analysis (p=0.029; HR 1.51; 95%CI 1.04−2.18); interestingly, no difference in response to chemotherapy was found between patients with and without sarcopenia (p=0.583).
Some articles have analyzed the presence of myokines, which are proteins produced by skeletal muscle with potential anticancer effects. This hypothesis could have a major impact in terms of prehabilitation and postoperative management if a targeted therapy could be found 1,17 .
The present article has the following limitations: 1. Small sample size: The main reason was the lack of CT scans done in our institution; most gastric patients operated on during that period had topographies from different radiological centers. This limitation may have some role in the multivariate analysis and the magnitude of prognostic power.

2.
Lack of complementary nutritional studies: Even though tomographic assessment for sarcopenia has been validated, the aim of this study was not to compare this tool with other nutritional diagnostic methods. The additional information would have been valuable to define, whereas the condition of sarcopenia was used not only as the tomographic tool but also as a prognostic variable in this population.

3.
Lack of SMI: The database used did not have weight measurements to calculate body surface in more than 80% of patients so that index was impossible to assess.

CONCLUSION
The findings in this report suggest that PD has a strong prognostic value in predicting leakage of the EJJ and overall 5-year long-term survival, with 32 and 37 HU being the optimal cutoff points, respectively.
More efforts should be needed in Caucasian, North American, and Latin American countries to study tomographic sarcopenia, in order to assess not only the efficacy of prognostic value but also the optimal cutoff points for that specific population.  Table 5 -Studies of gastric patients operated with curative intent, analyzed by tomographic sarcopenia.
*As the univariate analysis showed that neither psoas muscle cross-sectional area nor psoas muscle density had any prognostic value on morbidity, the rate expresses the frequency of morbidity in the whole group.